Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial

Ingmar Blümcke^{1

2}, Roland Coras¹, Robyn M Busch^{2

3

4}, Marcia Morita-Sherman², Dennis Lal^{2

4}, Richard Prayson⁵, Fernando Cendes^{6

7}, Iscia Lopes-Cendes^{7

8}, Fabio Rogerio^{7

9}, Vanessa S Almeida^{7

8}, Cristiane S Rocha^{7

8}, Nam Suk Sim¹⁰, Jeong Ho Lee^{10

11}, Se Hoon Kim¹², Stephanie Baulac¹³, Sara Baldassari¹³, Homa Adle-Biassette^{14

15}, Christopher A Walsh^{16

17}, Sara Bizzotto^{16

17}, Ryan N Doan^{16

17}, Katherine S Morillo^{16

17}, Eleonora Aronica^{18

19}, Angelika Mühlebner^{18

20}, Albert Becker²¹, Jesus Cienfuegos^{22

23}, Rita Garbelli²⁴, Caterina Giannini^{25

26}, Mrinalini Honavar²⁷, Thomas S Jacques^{28

29}, Maria Thom³⁰, Anita Mahadevan³¹, Hajime Miyata³², Pitt Niehusmann³³, Harvey B Sarnat^{34

35

36}, Figen Söylemezoglu³⁷, Imad Najm^{2

3}

Affiliations

¹ Department of Neuropathology, University Hospital, Erlangen, Germany.
² Epilepsy Center, Cleveland Clinic, Cleveland, OH, USA.
³ Department of Neurology, Cleveland Clinic, Cleveland, OH, USA.
⁴ Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
⁵ Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
⁶ Department of Neurology, University of Campinas, Sao Paulo, Brazil.
⁷ Brazilian Institute of Neuroscience and Neurotechnology, Sao Paulo, Brazil.
⁸ Department of Medical Genetics and Genomic Medicine, University of Campinas, Sao Paulo, Brazil.
⁹ Department of Pathology, University of Campinas, Sao Paulo, Brazil.
¹⁰ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
¹¹ SoVarGen, Inc., Daejeon, Korea.
¹² Department of Pathology, College of Medicine, Yonsei University, Seoul, South Korea.
¹³ Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Paris, France.
¹⁴ Pathological Anatomy Service, Public Hospital Network of Paris, Paris, France.
¹⁵ NeuroDiderot, Inserm U1141, University of Paris, Paris, France.
¹⁶ Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
¹⁷ Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA.
¹⁸ Department of (Neuro)Pathology, Amsterdam UMC, location Academic Medical Center, Amsterdam, the Netherlands.
¹⁹ Epilepsy Institutes of the Netherlands Foundation, Heemstede, the Netherlands.
²⁰ Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
²¹ Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
²² Department of Anatomic Pathology, International Center for Epilepsy Surgery, Humanitas Medical Group Hospital, Mexico City, Mexico.
²³ Department of Anatomic Pathology, Angels Mexico Hospital, Mexico City, Mexico.
²⁴ Epilepsy Unit, Carlo Besta Neurological Institute, Scientific Institute for Research and Health Care Foundation, Milan, Italy.
²⁵ Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.
²⁶ Department of Biomedical and Neuromotor Science,, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
²⁷ Department of Anatomic Pathology, Pedro Hispano Hospital, Matosinhos, Portugal.
²⁸ Developmental Biology and Cancer Research and Teaching Programme, University College London Great Ormond Street Institute of Child Health, London, UK.
²⁹ Department of Histopathology, Great Ormond Street Hospital for Children, National Health Service Foundation Trust, London, UK.
³⁰ Department of Neuropathology, Institute of Neurology, University College London, London, UK.
³¹ Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India.
³² Department of Neuropathology, Research Institute for Brain and Blood Vessels, Akita Cerebrospinal and Cardiovascular Center, Akita, Japan.
³³ Department of Neuro-/Pathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Oslo, Norway.
³⁴ Department of Paediatrics, University of Calgary Faculty of Medicine, Alberta Children's Hospital Research Institute, Calgary, AB, Canada.
³⁵ Department of Pathology (Neuropathology),, University of Calgary Faculty of Medicine, Alberta Children's Hospital Research Institute, Calgary, AB, Canada.
³⁶ Department of Clinical Neurosciences, University of Calgary Faculty of Medicine, Alberta Children's Hospital Research Institute, Calgary, AB, Canada.
³⁷ Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

PMID: 33949696
DOI: 10.1111/epi.16899

Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial

Ingmar Blümcke et al. Epilepsia. 2021 Jun.

. 2021 Jun;62(6):1416-1428.

doi: 10.1111/epi.16899. Epub 2021 May 5.

Authors

Affiliations

¹ Department of Neuropathology, University Hospital, Erlangen, Germany.
² Epilepsy Center, Cleveland Clinic, Cleveland, OH, USA.
³ Department of Neurology, Cleveland Clinic, Cleveland, OH, USA.
⁴ Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
⁵ Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
⁶ Department of Neurology, University of Campinas, Sao Paulo, Brazil.
⁷ Brazilian Institute of Neuroscience and Neurotechnology, Sao Paulo, Brazil.
⁸ Department of Medical Genetics and Genomic Medicine, University of Campinas, Sao Paulo, Brazil.
⁹ Department of Pathology, University of Campinas, Sao Paulo, Brazil.
¹⁰ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
¹¹ SoVarGen, Inc., Daejeon, Korea.
¹² Department of Pathology, College of Medicine, Yonsei University, Seoul, South Korea.
¹³ Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Paris, France.
¹⁴ Pathological Anatomy Service, Public Hospital Network of Paris, Paris, France.
¹⁵ NeuroDiderot, Inserm U1141, University of Paris, Paris, France.
¹⁶ Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
¹⁷ Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA.
¹⁸ Department of (Neuro)Pathology, Amsterdam UMC, location Academic Medical Center, Amsterdam, the Netherlands.
¹⁹ Epilepsy Institutes of the Netherlands Foundation, Heemstede, the Netherlands.
²⁰ Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
²¹ Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
²² Department of Anatomic Pathology, International Center for Epilepsy Surgery, Humanitas Medical Group Hospital, Mexico City, Mexico.
²³ Department of Anatomic Pathology, Angels Mexico Hospital, Mexico City, Mexico.
²⁴ Epilepsy Unit, Carlo Besta Neurological Institute, Scientific Institute for Research and Health Care Foundation, Milan, Italy.
²⁵ Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.
²⁶ Department of Biomedical and Neuromotor Science,, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
²⁷ Department of Anatomic Pathology, Pedro Hispano Hospital, Matosinhos, Portugal.
²⁸ Developmental Biology and Cancer Research and Teaching Programme, University College London Great Ormond Street Institute of Child Health, London, UK.
²⁹ Department of Histopathology, Great Ormond Street Hospital for Children, National Health Service Foundation Trust, London, UK.
³⁰ Department of Neuropathology, Institute of Neurology, University College London, London, UK.
³¹ Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India.
³² Department of Neuropathology, Research Institute for Brain and Blood Vessels, Akita Cerebrospinal and Cardiovascular Center, Akita, Japan.
³³ Department of Neuro-/Pathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Oslo, Norway.
³⁴ Department of Paediatrics, University of Calgary Faculty of Medicine, Alberta Children's Hospital Research Institute, Calgary, AB, Canada.
³⁵ Department of Pathology (Neuropathology),, University of Calgary Faculty of Medicine, Alberta Children's Hospital Research Institute, Calgary, AB, Canada.
³⁶ Department of Clinical Neurosciences, University of Calgary Faculty of Medicine, Alberta Children's Hospital Research Institute, Calgary, AB, Canada.
³⁷ Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

PMID: 33949696
DOI: 10.1111/epi.16899

Abstract

Objective: Focal cortical dysplasia (FCD) is a major cause of difficult-to-treat epilepsy in children and young adults, and the diagnosis is currently based on microscopic review of surgical brain tissue using the International League Against Epilepsy classification scheme of 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas of diagnostic challenges in this widely used classification scheme.

Methods: Four web-based digital pathology trials were completed by 20 neuropathologists from 15 countries using a consecutive series of 196 surgical tissue blocks obtained from 22 epilepsy patients at a single center. Five independent genetic laboratories performed screening or validation sequencing of FCD-relevant genes in paired brain and blood samples from the same 22 epilepsy patients.

Results: Histopathology agreement based solely on hematoxylin and eosin stainings was low in Round 1, and gradually increased by adding a panel of immunostainings in Round 2 and the Delphi consensus method in Round 3. Interobserver agreement was good in Round 4 (kappa = .65), when the results of genetic tests were disclosed, namely, MTOR, AKT3, and SLC35A2 brain somatic mutations in five cases and germline mutations in DEPDC5 and NPRL3 in two cases.

Significance: The diagnoses of FCD 1 and 3 subtypes remained most challenging and were often difficult to differentiate from a normal homotypic or heterotypic cortical architecture. Immunohistochemistry was helpful, however, to confirm the diagnosis of FCD or no lesion. We observed a genotype-phenotype association for brain somatic mutations in SLC35A2 in two cases with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Our results suggest that the current FCD classification should recognize a panel of immunohistochemical stainings for a better histopathological workup and definition of FCD subtypes. We also propose adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype-phenotype diagnosis in the near future.

Keywords: brain; classification; epilepsy; genes; neuropathology; seizure.

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References

REFERENCES

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1. Lamberink HJ, Otte WM, Blümcke I, Braun KPJ, Aichholzer M, Amorim I, et al. Seizure outcome and use of antiepileptic drugs after epilepsy surgery according to histopathological diagnosis: a retrospective multicentre cohort study. Lancet Neurol. 2020;19:748-57.
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Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial

Affiliations

Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous